The R562S-Kv7.1 variant was associated with significantly prolonged QTc intervals at rest and after exercise compared to healthy relatives, due to impaired response to β-adrenergic stimulation.
Observational
The R562S-Kv7.1 variant is the first identified in helix C that impairs the IKs channel's response to β-adrenergic stimulation, explaining exercise-induced arrhythmias in carriers and suggesting mild ICa inhibition as a potential therapy.
Abstract Background and Aims Kv7.1 variants, associated with long-QT syndrome type 1 (LQT1) and altering the function of the slow delayed rectifier K+ (IKs) channel, may result in arrhythmias, especially during exercise. This study focused on complex analysis of the R562S-Kv7.1 variant located in helix C of the Kv7.1 C-terminus, which was identified in four putatively unrelated families in the Czech Republic. Methods The clinical and genetic investigation was followed by functional analysis (whole-cell patch clamp, confocal microscopy, computational simulations) and structural modelling. Results The genetic analysis suggested that R562S-Kv7.1 might be a founder LQT1 variant in Central Europe. R562S carriers showed a significantly prolonged QTc interval at rest and a significantly higher QTc prolongation after exercise vs. healthy relatives. The functional analysis of R562S channels demonstrated their preserved membrane localization, a significant decrease in IKs with a rightward shift of the voltage dependence of activation, and, importantly, a lack of responsiveness to β-adrenergic stimulation. The latter seems to be related to a modified interaction of the modulatory KCNE1 subunit with Kv7.1. The proarrhythmic potential of R562S dysfunction, mediated by delayed afterdepolarizations during β-adrenergic stimulation, could be effectively prevented by mild (5%) inhibition of L-type Ca2+ current (ICa). Conclusion R562S-Kv7.1 is the first variant in helix C causing an impaired response of IKs channel to β-adrenergic stimulation, likely due to altered interactions between channel subunits, namely Kv7.1 and KCNE1. Mild ICa inhibition was suggested as a new treatment option.
Král et al. (Tue,) conducted a observational in Long-QT syndrome type 1 (LQT1). R562S-Kv7.1 variant vs. Healthy relatives was evaluated on QTc interval at rest and after exercise. The R562S-Kv7.1 variant was associated with significantly prolonged QTc intervals at rest and after exercise compared to healthy relatives, due to impaired response to β-adrenergic stimulation.